Divergent reactivity of α-oximino carbenoids: Facile access to 2-isoxazolines and 2H-azirines

Article abstract of DOI:10.1039/c1cc11683e

Mild catalytic reaction conditions for the synthesis of 2-isoxazolines and 2H-azirines have been developed via carbenoids derived from α-oximino diazo compounds. This has been utilized in the one-pot synthesis of pyrroles in the presence of 1,3-dicarbonyl

Full text of DOI:10.1039/c1cc11683e

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COMMUNICATION
Divergent reactivity of a-oximino carbenoids: facile access
to 2-isoxazolines and 2H-azirinesw
Xinxin Qi,z Yaojia Jiangz and Cheol-Min Park*
Received 24th March 2011, Accepted 20th May 2011
DOI: 10.1039/c1cc11683e
Mild catalytic reaction conditions for the synthesis of 2-isoxazolines
and 2H-azirines have been developed via carbenoids derived
from a-oximino diazo compounds. This has been utilized in the
one-pot synthesis of pyrroles in the presence of 1,3-dicarbonyl
compounds.
The reactivity of metallocarbenoids has been extensively utilized
in the development of new synthetic methods including C–H
insertion, addition and ylide formation.1 The versatile reactivity
of carbenoids allows for effecting various types of bond
formation that are otherwise difficult to be realized. Function-
alization of inert C–H bonds has recently drawn a great deal of
attention which offers advantages such as increased synthetic
efficiency and benign environmental impact.2 Carbenoid-
mediated C–H insertion has been extensively exploited in the
formation of new C–C bonds.3 While offering a powerful
means for C–C bond formation, it has been largely limited
to carbenoids derived from a-diazocarbonyl compounds.4
On the other hand, the potential of their nitrogen analogues,
a-imino carbenoids remains to be explored. The introduction
of nitrogen atoms adjacent to carbenoids would provide direct
access to nitrogen-embedded products. While isomerization
of a-imino diazo compounds to triazoles results in loss of
reactivity in metal-catalyzed generation of carbenoids,5 Fokin
and co-workers recently reported a method to generate a-imino
carbenoids from triazoles.6 In this regard, we have also reported
a method that allows for the preparation of a-oximino diazo
compounds without isomerization to triazoles, and their utility
as carbenoid precursors in the synthesis of N-alkoxypyrroles
via [3 + 2] cycloaddition reaction.7 In our continued efforts to
explore their reactivity, Sintim and co-workers reported the
development of C–H insertion reaction of a-diazo carbonyl
compounds containing an N–O moiety.8 Herein, we wish to
describe the divergent reactivity of carbenoids derived from
a-oximino diazo compounds leading to the formation of
2-isoxazolines and 2H-azirines (Fig. 1).
Fig. 1 Divergent reactivity of a-diazo oxime ethers.
Isoxazolines and azirines represent important classes of hetero-
cycles that are widely found in drug molecules, natural products
and synthetic intermediates. 2-Isoxazolines are, in general,
synthesized by 1,3-dipolar cycloaddition of nitrile oxides,9
and Michael addition of hydroxylamines.10 The highly strained
reactive heterocycle 2H-azirines have proven to be very useful
intermediates in a number of synthetic transformations.11 It
has been shown that strain-driven ring opening of 1-azirine
derivatives results in the generation of nitrenes which sub-
sequently undergo C–H insertion to form indoles.12 The electro-
philic nature of 2H-azirines allows for facile nucleophilic
additions and cycloadditions providing efficient routes for the
synthesis of various heterocycles such as aziridines, indoles,
isoxazoles, oxazolines and pyrazines. While considering the
versatile utility of 2H-azirines, the availability of synthetic
methods is rather limited, largely relying on the Neber reaction
that employs strong bases.13 Other approaches include thermal
rearrangement of vinyl azides,14 oxidation of aziridines15 and
addition of carbenes/nitrenes across nitriles/alkynes16 albeit with
moderate success.
During our investigation of the reactivity of a-oximino
carbenoids, we observed facile intramolecular C–H insertion
of oxime ether moieties resulting in the formation of 2-isoxazolines
in good yields. Encouraged by these observations, we examined
the catalytic activity of various catalysts employing compound 1a
as a substrate (Table 1). While the use of copper salts resulted
in poor yields, screening of rhodium salts gave more promising
results with the formation of 2-isoxazoline 2a as the major product
along with varying amounts of 2H-azirine 3a.17 Examination
of the influence of steric and electronic properties of ligands
revealed that rhodium complexes with electron deficient ligands
Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371,
Singapore. E-mail: cmpark@ntu.edu.sg; Fax: +65-6513-2748;
Tel: +65-6513-2748
w Electronic supplementary information (ESI) available: Detailed experi-
mental procedures and analytical data. See DOI: 10.1039/c1cc11683e
z XQ and YJ contributed equally.
c
7848 Chem. Commun., 2011, 47, 7848–7850
This journal is The Royal Society of Chemistry 2011

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Table 1 Screening of catalysts and solvents
noted that the electronic influence of substituents has a
profound impact on determining the reaction pathway. Hence,
substrates with electron withdrawing groups adjacent to oxime
ethers strongly favor C–H insertion resulting in the formation
of 2-isoxazolines as major products (Table 2, entries 1–7),
whereas those substituted with alkyl groups favor formation
of 2H-azirines as major products (Table 2, entries 8–14).
Comparison of the reactivity of oxime ethers bearing a
cycloalkane with an acyclic group showed a preference for a
cycloalkane (Table 2, entries 1 vs. 2). The substrate bearing
benzyl ether afforded a mixture of cis/trans-2-isoxazolines18 in
a ratio of 1.4 : 1 in 65% yield along with a minor amount of
2H-azirine (Table 2, entry 3). Alteration of the electronics of
benzyl groups sheds light on the electronic impact of C–H
bonds undergoing insertion (Table 2, entries 3–6). Contrary
to the general preference of carbenoid-mediated insertion
for electron-rich C–H bonds,19 it is of note that a reversed
trend was observed with substrates bearing electron-poor C–H
bonds affording products in higher yields and selectivities.
Meanwhile, C–H insertion on 1g smoothly proceeded to
Yieldc
Solventb Temp./1C Ratioc (2a/3a) (%) 2a
Entry Catalysta
1
2
3
4
5
6
7
8
Cu(OTf)2
Cu(acac)2
Rh2(OAc)4
Rh2(TFA)4
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
40
60
80
100
—
—
2.3 : 1
—
1 : 2
0
0
56
0
10
0
49
51
59
59
47
38
48
53
Rh2(tfacam)4 DCE
Rh2(pfb)4
Rh2(Hex)4
Rh2(Oct)4
Rh2(esp)4
Rh2(Piv)4
Rh2(Piv)4
Rh2(Piv)4
Rh2(Piv)4
Rh2(Piv)4
DCE
DCE
DCE
DCE
DCE
DCM
CHCl3
PhH
—
3 : 1
1.6 : 1
3.8 : 1
15 : 1
420 : 1
420 : 1
420 : 1
420 : 1
9
10
11
12
13
14
PhCF3
a
acac = acetylacetonate, TFA = trifluoroacetate, tfacam = trifluoro-
acetamide, pfb = perfluorobutyrate, Hex = hexanoate, Oct = octanoate,
esp = a,a,a0,a0-tetramethyl-1,3-benzenedipropionate, Piv = pivaloate.
give the product with
(Table 2, entry 7).20
a quaternary stereogenic center
b
c
With these results in hand, we turned our attention to the
formation of 2H-azirines. A brief survey of substrates revealed
that those bearing electron donating groups adjacent to oximes
(R1) provide 2H-azirines via displacement of alkoxy groups on
oxime ethers. Thus, when 1h bearing a methyl group was
treated with 2 mol% Rh2(Piv)4 at RT, a rapid formation of
2H-azirine 3h was observed in 60% yield along with 2-oxazoline
2h in 20% yield (Table 2, entry 8). Subsequent examination
of the substitution on the ether moieties revealed that an
isopropyl group is optimal for the 2H-azirine formation,
presumably due to its high propensity as a leaving group.
On the other hand, examination of the substitution adjacent to
oximes showed (R1) that various alkyl groups are tolerated
DCE = dichloroethane, DCM = dichloromethane. Determined by
NMR vs. standard.
give poor results (Table 1, entries 4–6). Gratifyingly, the use of
Rh2(OAc)4, Rh2(esp)4 or Rh2(Piv)4 afforded 2a in good yields
(Table 1, entries 3, 9, 10). Notably, an improvement of
the selectivity for 2a over 3 could be achieved with the use
of Rh2(Piv)4 (Table 1, entry 10). Furthermore, screening of
various solvents indicated dichloroethane as an optimal
solvent.
With the optimized reaction conditions in hand, we investi-
gated the substrate scope of the reaction (Table 2). It was
Table 2 Synthesis of 2-isoxazolines and 2H-azirines
Entrya,b
1
R1
R2
R3
R4
Yieldc (%) 2 + 20 (2 : 20)d
Yieldc (%) 3
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CH3
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Bn
CO2Me
CO2tert-Bu
CO2Me
CO2Me
CO2Me
CO2Me
(CH2)5
CH3
Ph
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
Ph
CH3
CH3
CH3
CH3
60
46
4
6
CH3
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
65 (1.4 : 1)
63 (1.7 : 1)
50 (1 : 1.2)
73 (2.4 : 1)
50 (2.5 : 1)
20
16
16
23
20
21
23
24
21
30
16
27
60
63
56
61
53
51
62
9
Bn
Bn
10
11
12
13
14
4-MeOC6H4CH2
4-ClC6H4CH2
3-ClC6H4CH2
PhCH2CH2
CH3
CH3
CH3
a
b
Entries 1–7; reflux, 2 h. Entries 8–14; RT, 3–12 h. Yields of isolated products. Ratios determined by NMR.
c
d
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7848–7850 7849

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In summary, we have described the development of the catalytic
methods under mild reaction conditions for the synthesis of highly
valuable heterocycles such as 2-isoxazolines and 2H-azirines.
Furthermore, the development of a one-pot tandem reaction for
pyrrole synthesis was achieved where the formation of 2H-azirine
is promoted by the rhodium complex followed by reaction with
1,3-diketone.
We gratefully acknowledge Nanyang Technological University
Start Up Grant and Tier 1 Grant RG 25/09 for the funding of
this research.
c
7850 Chem. Commun., 2011, 47, 7848–7850
This journal is The Royal Society of Chemistry 2011